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The presence of single nucleotide polymorphisms (SNPs) in the RET (REarranged during Transfection) gene has been investigated with regard to their potential role in the development or progression of medullary thyroid cancer (MTC) or pheochromocytomas (PHEO) in patients with the multiple endocrine neoplasia type 2 (MEN2) syndrome. The aim of this study was to evaluate the spectrum of RET variants in France between 2003 and 2013, and an evaluation of the impact of SNPs on the MEN2 A phenotype.In this retrospective cohort study RET variants were screened in 5109 index cases and RET pathogenic variants were screened in 2214 relatives. Exons 5, 8, 10, 11, 13, 14, 15 and 16 were characterized by Sanger sequencing. RET pathogenic variants, RET variants with unknown functional effects (VUS) and four RET SNPs variants i.e. G691S (rs1799939), L769L (rs1800861), S836S (rs1800862), and S904S (rs1800863) were reported in index cases. In silico analysis and classification following the recommendation of the ACMG (American College of Medical Genetics and Genomics) was performed for RET variants with unknown functional effects. Each patient's age at the time of diagnosis, sex, and the endocrine neoplasias present at molecular diagnosis were recorded.Twenty-six single VUS in RET without any well-defined risk profiles were found in 33 patients. Nine of these were considered probably pathogenic, 11 of uncertain significance, and 6 as probably benign. Three double pathogenic variants found in 3 patients were classified as pathogenic. A study of the entire cohort showed that patients carrying pathogenic variants or VUS in RET together with PHEO were diagnosed earlier than the others. The presence of the G691S SNP, or a combination of SNPs, increased the risk of developing PHEO, but did not modify the date of the diagnosis. No association was found between SNPs and medullary thyroid cancer (MTC) or hyperparathyroidism (HPTH).Our finding propose a classification of 15 of the 26 VUS in RET without any well-defined risk profiles and suggest that the G691S SNP, or a combination of SNPs, may be associated with the development of PHEO.

Nationwide French Study of RET Variants Detected from 2003 to 2013 Suggests a Possible Influence of Polymorphisms as Modifiers